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B. Luey
Moderator of
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ORAL 31 - PD1 Axis Inhibition (ID 143)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 8
- Moderators:J. Weiss, B. Luey
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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ORAL31.01 - PD-L1 Expression as Predictive Biomarker in Patients with NSCLC: A Pooled Analysis (ID 1578)
16:45 - 16:56 | Author(s): F. Passiglia, G. Bronte, S. Rizzo, A. Galvano, G. Sortino, E. Musso, A. Listì, N. Barraco, M. Castiglia, V. Calò, V. Bazan, G. Cicero, C. Rolfo, A. Russo
- Abstract
- Presentation
Background:
Clinical trials of immune checkpoints modulators, including both programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, have recently shown promising activity and tolerable toxicity in pre-treated NSCLC patients. However the predictive role of PD-L1 expression is still controversial. This pooled analysis aims to clarify the association of clinical objective responses to anti PD-1/PD-L1 monoclonal antibodies (MoAbs) and PD-L1 expression in pre-treated NSCLC patients.
Methods:
Data from all published studies, that evaluated efficacy and safety of PD-1/PD-L1 inhibitors in pre-treated NSCLC patients, stratified by tumor PD-L1 expression status (immunohistochemistry, cut-off point 1%), were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, and World Conference of Lung Cancer, meeting proceedings. Pooled Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated for the Overall Response Rate (ORR) (as evaluated by Response Evaluation Criteria in Solid Tumors, version 1.1), according to PD-L1 expression status.
Results:
A total of six studies, with 776 patients, were eligible. Pooled analysis showed that patients with PD-L1 positive tumors (PD-L1 tumor cell staining ≥1%), had a significantly higher ORR, compared to patients with PD-L1 negative tumors (OR: 2.53; 95% CIs: 1.65-3.87). Figure 1Figure 2
Conclusion:
PD-L1 tumor expression seems to be associated with clinical activity of anti PD-1/PD-L1 MoAbs, in pre-treated, NSCLC patients, suggesting a potential role of PD-L1 expression, IHC cut-off point 1%, as predictive biomarker for the selection of patients who may benefit more from these therapies. Further analysis from ongoing phase II/III clinical trials will provide more information about this observation.
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ORAL31.02 - Pembrolizumab for NSCLC: Immune-Mediated Adverse Events and Corticosteroid Use (ID 3032)
16:56 - 17:07 | Author(s): N. Leighl, L. Gandhi, M.D. Hellmann, L. Horn, M. Ahn, E.B. Garon, R. Hui, S.S. Ramalingam, J. Zhang, G. Lubiniecki, H. Raftopoulos, O. Hamid
- Abstract
- Presentation
Background:
Pembrolizumab is a humanized monoclonal antibody against PD-1 that has demonstrated robust antitumor activity and a manageable safety profile in patients with advanced malignancies, including NSCLC. Similar to other immune checkpoint inhibitors, immune-mediated toxicities have been observed with pembrolizumab. We characterized the incidence of potentially immune-mediated adverse events (AEs) and the use of systemic corticosteroids for their management in patients with NSCLC treated with pembrolizumab in the phase 1 KEYNOTE-001 trial (ClinicalTrials.gov, NCT01295827).
Methods:
550 patients with advanced NSCLC received pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or 10 mg/kg every 2 weeks (Q2W). Potentially immune-mediated AEs were derived from a prespecified list and considered regardless of attribution to study treatment by the investigator. High-dose corticosteroid use was defined as an initial dose of ≥40 mg/day prednisone or equivalent. Low-dose corticosteroid use was defined as an initial dose of <40 mg/day prednisone or equivalent.
Results:
71 (12.9%) patients experienced ≥1 immune-mediated AE, including 17 (3.1%) who experienced grade 3-4 events, 1 (0.2) who died because of an immune-mediated AE (pneumonitis), and 14 (2.5%) who discontinued pembrolizumab because of immune-mediated AEs. The median time to onset of the first immune-mediated AE was 104 days (range, 2-393 days). Immune-related AE incidence was similar in patients treated with pembrolizumab 10 mg/kg Q2W and Q3W. The most common immune-mediated AEs were hypothyroidism, pneumonitis, and infusion-related reactions (Table). Pneumonitis was the most common grade 3-4 toxicity. Excluding hypothyroidism, 74.2% of immune-mediated AEs had resolved at the time of data cutoff. Of the 71 patients who experienced immune-mediated AEs, 30 (42.2%) received corticosteroids: 20 received high dose, 10 low dose. The highest incidence of corticosteroid use was for pneumonitis (84.2%) and colitis (80.0%) (Table). The duration of initial steroid use ranged from 1 to 129 days. Analyses related to the impact of steroid use on pembrolizumab efficacy are ongoing and will be available for presentation. Figure 1
Conclusion:
Potentially immune-mediated AEs, particularly those of grade 3-5 severity, are relatively infrequent in patients with advanced NSCLC treated with pembrolizumab. As evidenced by the low rate of pembrolizumab discontinuation, most immune-mediated events were managed by temporary pembrolizumab interruption and corticosteroid use.
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ORAL31.03 - Evaluation of Disease-Related Symptoms in Patients with Advanced Squamous Non-Small Cell Lung Cancer Treated with Nivolumab or Docetaxel (ID 743)
17:07 - 17:18 | Author(s): R.J. Gralla, C. Coon, F. Taylor, J.R. Penrod, M. DeRosa, H. Dastani, L. Orsini, M. Reck
- Abstract
- Presentation
Background:
The CheckMate 017 (NCT01642004) randomized, open-label, global phase 3 study evaluated efficacy and safety of second-line nivolumab vs docetaxel in patients with advanced squamous (SQ) non-small cell lung cancer (NSCLC). Overall survival was significantly superior and duration of treatment longer for nivolumab vs docetaxel. The study also evaluated disease-related symptoms using the Lung Cancer Symptom Scale (LCSS).
Methods:
The LCSS includes 100 mm visual analog scales for 6 major lung cancer symptoms plus three global items evaluating the impact of symptoms; 0 represents the least severity and 100 the greatest severity. Assessment was performed every 4 weeks for nivolumab and every 3 weeks for docetaxel for the first 6 months on treatment, followed by every 6 weeks for the remainder of the treatment period for both study arms. Following treatment discontinuation, the LCSS also was assessed at two follow-up visits. The LCSS average symptom burden index (ASBI) was computed from the 6 individual symptom scores. Mean baseline and mean change from baseline of the LCSS ASBI at each assessment were summarized by treatment group. A study secondary endpoint was to estimate the proportion of patients whose LCSS ASBI showed a clinically meaningful improvement by week 12 (10 point or greater decrease, the minimally important difference [MID]), which was based on all randomized patients.
Results:
Patient baseline characteristics were generally balanced across treatment groups. LCSS completion rates for baseline and at least one subsequent assessment were 68.9% and 62.8% for nivolumab and docetaxel, respectively. Completion rates remained relatively consistent throughout assessments and by treatment arm. Baseline LCSS ASBI values were similar for nivolumab (29.6; standard deviation [SD] 16.4) and docetaxel (29.6; SD 14.7). By week 12, 20.0% (27/135; 95% CI: 13.6, 27.7) of nivolumab patients demonstrated clinically meaningful symptom improvement compared to 21.9% (30/137; 95% CI: 15.3, 29.8) of docetaxel patients. Examining mean changes from baseline in patients’ LCSS ASBIs at each assessment, the nivolumab group demonstrated statistically significant improvements from baseline at each assessment from week 12 through week 54, after which sample sizes dropped to fewer than 10 patients; from week 40 through 54, the mean improvements exceeded the MID. In contrast, docetaxel patients remaining on treatment had no statistically significant changes in LCSS ASBI through week 18, after which the sample dropped to fewer than 10 patients. In the two follow-up visits after treatment discontinuation, the mean of the LCSS ASBI for both nivolumab and docetaxel patients indicated similar worsening of symptoms relative to baseline (range, 5.5–9.5); for docetaxel patients, the differences from baseline were statistically significant.
Conclusion:
By week 12, the proportion of patients showing meaningful symptom improvement was similar for both the nivolumab and docetaxel groups. However, the overall average symptom burden while on nivolumab improved from baseline over most of the year of available follow up, while average symptom burden for docetaxel patients remained stable relative to baseline during their shorter time on treatment. These results show statistically and clinically significant reductions from baseline in lung cancer symptoms for patients with squamous NSCLC treated with second-line nivolumab.
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ORAL31.04 - Discussant for ORAL31.01, ORAL31.02, ORAL31.03 (ID 3367)
17:18 - 17:28 | Author(s): K. Kelly
- Abstract
- Presentation
Abstract not provided
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ORAL31.05 - High Intratumoral T Cell Infiltration Correlated with Mutational Load and Response to Pembrolizumab in Non-Small Cell Lung Cancer (ID 2728)
17:28 - 17:39 | Author(s): S. Hu-Lieskovan, J.W. Goldman, M. Han, J. Zaretsky, I. Shintaku, B. Wolf, P. Abarca, T. Walser, A. Lisberg, D.J. Slamon, S.M. Dubinett, A. Ribas, E.B. Garon
- Abstract
- Presentation
Background:
Responses to PD-1 blockade have been induced in approximately 20% of advanced non-small cell lung cancer (NSCLC) patients with progressive disease after standard therapy [Garon, NEJM 2015]. One challenge is to understand how the immune response was initiated in responding patients. Tumor mutational burden has been associated with response to PD-1 checkpoint inhibitors in NSCLC [Rizvi, Science, 2015]. In addition, studies in melanoma patient-derived tumor specimens revealed that responses to PD-1/L1 blockade rely on pre-therapy tumor infiltration of activated T effector cells [Tumeh, Nature, 2014]. We hypothesize that clonal T cell infiltration is correlated with tumor mutational load and clinical response with PD-1 blockade.
Methods:
We studied tumor specimens in NSCLC patients treated with pembrolizumab at UCLA on the KEYNOTE -001 clinical trial. All patients signed informed consent for the trial as well as separate specimen acquisition protocols. Responses were classified by the investigators according to irRC. DNA was extracted and whole exome sequencing was performed at the UCLA Immunogenetics Core. DNA from the same patient’s PBMC or other non-cancerous tissue was sequenced for baseline comparison. Immunohistochemistry (IHC) was done for CD8 (Clone C8/144B, Dako), CD4 (Clone SP35, Cell Marque) and PD-L1 (Clone SP142, Spring Bioscience).
Results:
We report results from 27 patients (14 responders, and 13 nonresponders). Significantly higher density of pre-dosing CD8+ cells (percentage of CD8+ nucleated cells) in the tumors of the responding patients was observed (mean of 17.7% in responders vs 5.6% in non-responders, p=0.02 by unpaired t test) suggestive of a pre-existing immune response. Mutational load in 5 patients (3 responders and 2 nonresponders) showed a trend towards correlation with response (mean of 19 nonsynonymous somatic mutations per MB in responders vs 6 in nonresponders, p=0.33). Interestingly, a strikingly significant correlation between mutational load and CD8 expression was observed (R[2]=0.96, p=0.003). In addition, pre-dosing tumor PD-L1 expression demonstrated a trend towards correlation with response (mean of 72.1% in responders vs 51.5% in nonresponders, p=0.07) but not with CD8 tumor infiltration (R[2]=0.05, p=0.28). No significant association of CD4+ T cell tumor infiltration with response (mean of 37.4% CD4 + cells in responders vs 27.0% in nonresponders, p=0.32) was observed.
Conclusion:
We observed strong correlation of pre-dosing intratumoral T cell infiltration with response and mutational load in NSCLC patients treated with pembrolizumab. Our results have direct implications for the design and interpretation of ongoing and planned immunotherapy studies for NSCLC and evaluation of potential predictive biomarkers to select patients most likely to benefit.
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ORAL31.06 - An Exploratory Responder Analysis of Best RECIST Response and Survival in Patients with Metastatic Squamous NSCLC Treated with Nivolumab (ID 1701)
17:39 - 17:50 | Author(s): D. Kazandjian, G. Blumenthal, S. Khozin, L. Zhang, S. Tang, P. Keegan, R. Pazdur
- Abstract
- Presentation
Background:
New therapeutic modalities in metastatic squamous non-small cell lung cancer (SQ NSCLC) focus on targeting pathways (programmed cell death 1 [PD-1]) involved in inhibiting anti-tumor T cell responses leading to tumor evasion. Nivolumab, an anti-PD-1 monoclonal antibody, blocks T cell inhibitory signal pathways by preventing engagement of PD-1. On March 4, 2015, FDA approved nivolumab for the treatment of patients with metastatic SQ NSCLC with progression on or after platinum-based doublet chemotherapy. The approval was based on a randomized study (CA209017) demonstrating a large magnitude of improvement in overall survival (OS) and was supported by single arm study (CA209063) demonstrating a 15% objective response rate (ORR), which appeared to be durable. We conducted a retrospective exploratory responder analysis to evaluate the association between response and OS in study CA209063. Figure 1
Methods:
CA209063 was a multicenter, multinational, single-arm, open-label study in patients with SQ NSCLC who previously received at least two lines of systemic therapies. Patients (n=117) received nivolumab 3 mg/kg as an intravenous (IV) infusion every 2 weeks until progressive disease (PD) or toxicity; treatment past PD was allowed if certain “clinical benefit” criteria were met. Response was defined as a partial response (PR) or complete response (CR) as determined by a blinded independent review committee (IRC) utilizing the Response Evaluation Criteria In Solid Tumors (RECIST) criteria (98 of 117 were evaluable). Responders were categorized into the following groups: A CR or PR, stable disease (SD), PD with continuation of treatment, and PD with discontinuation of treatment. A sensitivity landmark-based analysis was performed to exclude timing of response evaluation bias (Anderson et al, 1983).
Results:
The exploratory responder analysis showed that patients who achieved a best response of CR or PR had the longest survival with anti-PD1 therapy, followed by patients who either achieved a best response of SD or PD with continuation of treatment beyond RECIST progression. Patients whose best response was PD and no treatment beyond progression had poor survival (figure 1). The Landmark time-based sensitivity analysis at 3.5 months (median time to response) also suggested that responders had longer survival than non-responders.
Conclusion:
Our analysis suggests that patients with NSCLC who respond are likely to derive the most clinical benefit from anti-PD1 therapy. However, given the exploratory retrospective nature of this analysis, results should be interpreted cautiously. Further development of predictive biomarkers to identify patients most likely to respond is necessary.
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ORAL31.07 - A Phase II Trial of Pembrolizumab for Untreated Brain Metastases from Non-Small Cell Lung Cancer (ID 824)
17:50 - 18:01 | Author(s): S.B. Goldberg, S.N. Gettinger, A. Mahajan, R. Herbst, A. Chiang, A.J. Tsiouris, A. Vortmeyer, L. Jilaveanu, S. Speaker, M. Madura, E. Rowen, H. Gerrish, X. Yao, V. Chiang, H. Kluger
- Abstract
- Presentation
Background:
Patients with advanced non-small cell lung cancer (NSCLC) often develop brain metastases (BrMs), and standard therapy such as surgery or radiation can cause toxicity and delay systemic treatment. Pembrolizumab is a PD-1 inhibitor with promising clinical activity and a favorable toxicity profile in patients with advanced NSCLC, however the efficacy of pembrolizumab in the central nervous system (CNS) is unknown. This trial aims to determine the safety and activity of pembrolizumab in patients with advanced NSCLC and untreated brain metastases.
Methods:
Eligibility for patients with NSCLC in this Phase II trial includes the presence of at least 1 BrM between 5 and 20 mm that is asymptomatic, untreated or progressing after prior local therapy, and not requiring urgent local therapy. PD-L1 expression in tumor obtained since the most recent systemic therapy is required. Patients are treated with pembrolizumab 10mg/kg every 2 weeks. Systemic response is determined by RECIST 1.1, and BrM response is determined by modified RECIST (mRECIST) in which brain lesions ≥ 5mm are considered measurable and up to 5 target lesions are allowed. The primary endpoint of this trial is BrM response rate.
Results:
Fifteen patients with NSCLC and untreated BrMs were treated with pembrolizumab, none of whom had a drug-related Grade ≥ 3 adverse event (AE) or any grade AE attributed to BrMs. Of the 10 patients evaluable for response, 5 (50% with 95% CI: 0.24-0.76) had a BrM response (4 partial and 1 complete) and 5 had a systemic response. Only one patient who responded in the body had progressive disease in the brain; all other patients who had a systemic response also had a CNS response. The duration of response in the brain was at least 12 weeks for 4 of the 5 responders, and all responses are ongoing at the time of data analysis.
Conclusion:
To our knowledge this is the first study to demonstrate that the PD-1 inhibitor pembrolizumab has activity in the CNS in patients with NSCLC and untreated brain metastases. To date there have been no drug-related neurologic or significant toxicity identified. Patient enrollment and biomarker analysis are ongoing.
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ORAL31.08 - Discussant for ORAL31.05, ORAL31.06, ORAL31.07 (ID 3368)
18:01 - 18:11 | Author(s): D.E. Gerber
- Abstract
- Presentation
Abstract not provided
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